Use for pain management

ABSTRACT

The present invention is directed to the intramuscular use of ropivacaine for the manufacture of a medicament for use in the treatment of muskuloskeletal pain, in particular myofascial pain and tendinitis.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 09/254,382,(now U.S. Pat. No. 6,395,291), filed on Mar. 2, 1999. Priority to the'382 application is claimed under 35 U.S.C. §120. application Ser. No.09/254,382 represents U.S. national stage of international applicationPCT/SE99/00012, which had an international filing date of Jan. 11, 1999,and which was published in English under Article 21(2) of the PCT onJul. 29, 1999. The international application claims priority to Swedishapplication 9800139-9, which was filed on Jan. 21, 1998.

FIELD OF THE INVENTION

The present invention is directed to the intramuscular use ofropivacaine for the manufacture of a medicament for use in the treatmentof muskuloskeletal pain, in particular myofascial pain and tendinitis.

BACKGROUND AND PRIOR ART

The most common diagnosis in most pain clinics is a disorder of skeletalmuscle and connective tissue origin, which may stem from previoustrauma, muscle tension or postural abnormalities. The two dominatingmuscle pain disorders are the generalized condition fibromyalgia and themainly localized myofascial pain.

Myofascial pain conditions are characterized by discrete tender lociknown as trigger points or tender points. These points are located byseveral methods including digital palpation or pressure pain thresholdalgometer testing and sometimes detection of skin loci with lowestelectrical independence.

The pathophysiology of human myofascial pain remains unknown. However,it has been suggested that myofascial tenderness may be the result of alowered pressure pain threshold, a stronger response to pressures in thenoxious range (Jensen K, Quantification of tenderness by palpation anduse of pressure algometers; In: friction Jr, Awad E., Advances in painResearch and Therapy, Vol. 17, Raven press, New York, 199, 1990, pp.165-181). The nociceptive processes are also qualitatively altered inpatients with chronic myofascial pain indicating that myofascial painmay be mediated by low-threshold mechanosensitive afferents projectingto sensitized dorsal horn neurons (Bendsten L., Jensen R, Oleson J.Qualitatively altered nociception in Chronic Myofascial pain, Pain 1996;65: pp. 259-264).

A wide range of therapeutic methods have been used over the years inorder to cure long lasting myofascial pain. The most commonly usedmethods have been massage, TENS, acupuncture, heat or cold packs,relaxation, unloading aching structures, traction and manipulation.Various analgesics, anti-inflammatory drugs and injected corticosteroidshave also been used. The various treatments often give initial relief ofpain but the pain often recurs, thereby necessitating repeatedtreatments.

In a double-blind study of myofascial pain syndrome (MPS), the effect onpain has been compared between bupivacaine (0.25%), lignocaine (1%), andsaline (Tschopp K P, Gysin C. Local Injection therapy in 107 patientswith myofascial pain syndrome of the head and neck; J. Oto-Rhino-Laryng& Rel. Spec. 1996; 58: 306-310). No significant difference between thesecompounds has, however, been reported.

OUTLINE OF THE INVENTION

The problem underlying the present invention was to find a new way oftreating muskuloskeletal pain, in particular myofascial pain andtendinitis. The inventors of the present invention have found that thelocal anaesthetic ropivacaine is useful for this treatment.

Ropivacaine refers to (S)-(−)-i-propyl-2′,6′-pipecoloxylididehydrochloride known to be useful for injection. It is described,including its long lasting local anesthetic effects, in EP 151 110 B1.In particular ropivacaine can be used in the form of its monohydrate inhigh enantiomeric purity, disclosed in EP 239 710 B1.

However, the routes of administration previously disclosed forropivacaine, are epidural administration, nerve block and peripheralinfiltration. Hitherto ropivacaine has not been disclosed for thetherapeutic use in accordance with the present invention.

The present invention is thus directed to a new use of ropivacaine forthe manufacture of a medicament for use in the treatment ofmuskuloskeletal pain, in particular myofascial pain.

The medical indication “muskuloskeletal pain” is a well establishedcondition, and will be appreciated by a person skilled in the art.

The medical indication “myofascial pain” is defined as a regional paincomplaint; pain complaint or alterred sensation in the expecteddistrubution of referred pain from a myofascial trigger point; taut bandpalpable in an accessible muscle; exquisite spot tenderness at one pointalong the length of the taut band; some degree of restricted range ofmotion, when measurable. A person skilled in the art will howeverappreciate the medical pain conditions belonging to this specific painindication.

A further specific medical condition which is within the scope of thedefinition of muskuloskeletal pain, is “tendinitis.” A person skilled inthe art will appreciate what patients belong to this group, but thefollowing can be mentioned as characteristic symptoms: regional pain;localized tenderness; increased pain on movement; and limited range ofmotion.

“Trigger point” (TP) is a focus of hyperirritability in a muscle or itsfascia that causes the patient pain. It causes referred pain andtenderness at rest, or with motion. The trigger point is always tender,and is located in a palpable band of muscle fibers. It prevents fulllengthening of the muscle. It usually weakens the muscle, refers pain ondirect compression, and mediates a local twitch response of the palpableband of muscle fibers when mechanically stimulated. Myofascial TPs caninitiate referred autonomic phenomena, which generally appear in thepain reference zone.

A further aspect of the present invention is a method for the treatmentof muskuloskeletal pain, in particular myofascial pain and tendinitis,whereby ropivacaine is administered intra-muscularly to a patientsuffering from said pain condition.

The active substance ropivacaine which is used in accordance with thepresent invention, is administered intra-muscularly by injection inmuscular “tender and/or trigger points”. A “tender point” is defined asa point over a muscle/tendon which is tender and elicits palpabralreflex on digital palpation. Although the definition of tender pointsand trigger points differ slightly, the two words are usedinterchangeably.

Ropivacaine is administered as a formulation suitable for intramuscularadministration and in an amount effective to ameliorate pain.

Accordingly, 0.1-10 ml ropivacaine is injected intramuscularly,preferably directly into each tender or trigger point. The concentrationof ropivacaine for administration intramuscularly is preferably 1-20mg/ml, and more preferably 2-10 mg/ml. A concentration as low as 2-5mg/ml may advantageously be used.

BIOLOGICAL EVALUATION

Ropivacaine hydrochloride 7.5 mg/ml solution for injection was used(Naropin®, Astra AB, Sweden). Ropivacaine was administered as a singledose intra-muscular tender point (TP) injection. Injection by means ofone needle insertion per tender point was preceded by aspiration beforeinfiltrating the study drug over the entire tender area. A standarddisposable syringe with a 0.4 mm diameter needle was used. Injectionrate was about 1 ml/30 sec. Injections were made at one occassion at avisit to the clinic. Follow-up data were obtained at a study end visitto the clinic 1 week after the injection.

(I) Patient Characteristics

Prior to the treatment the following information was recorded.

Demographic data: Date of birth, gender, race, body weight and height.

Past and current diagnoses: allergy and information related tosignificant past or present medical and surgical diagnoses excludingminor self-healing conditions with no obvious importance for the purposeof this study.

Current medication.

Active alcohol or drug abuse (yes/no).

A case history information including the duration of the presentorofacial muscle pain was collected. A clinical examination of theorofacial region including digital palpation of the temporomandibularjoints and masticatory muscles.

Ten patients (5 men and 5 women) whose age varied from 19 years to 69years (mean 42.9 years of age) were included in this test. The durationof complaints ranged from 1 month up to 10 years (mean 26.5 months).

All patients were subjected to unilateral injections of ropivacaine intotender points of the masseter muscle. Three patients received 1 ml, 5patients received 2 ml, 1 patient received 3 ml and 1 patient received 4ml of the study drug.

(II) Clinical Measurements

(i) Pain on maximal mouth opening

The patient rated their pain on a 100 mm visual analogue scale (VAS). Onthe VAS, 0 represents “no pain” and 100 represents “worst painimaginable”. The primary efficacy variable was VAS pain score at maximalmouth opening. The patient was asked to open the mouth as much aspossible and then they rated the experienced pain.

(ii) Pain at rest

The non-functional pain (jaw at rest) was also assessed by the patienton the VAS scale. This parameter was rated before the rating of pain onmaximal mouth opening.

(iii) Tender muscular points

A tender point was defined as point over a muscle/tendon which wastender and elicited a palpabral reflex on digital palpation. Bilateraldigital palpation of the temporalis muscle, the masseter muscle, thelateral pterygoid muscle and the temporalis tendon was used for theregistration of tender points. The number and site of injected tenderpoints and the total amount of the study drug used were recorded. Theassessment of tender muscle points was made prior to the assessment ofrange of movement.

(iv) Range of movement

The distance between the edges of the right upper and the correspondinglower medial incisor was used for the measurements of maximum mouthopening. Both maximum opening with and without pain was registered.

Results

The primary efficacy parameter, VAS rated pain at maximal mouth opening,showed a dramatic reduction as a result of the treatment. The median VASvalue at baseline was 59.5 mm compared to 6 mm at the follow-up. Thedata is shown in Table 1 below.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows that 6 out of the 10 patients became free or almost free oftheir muscular pain. Also the pain at rest decreased significantly asthe result of the treatment.

TABLE 1 Pain ratings using a 100 mm graded VAS at baseline and atfollow-up. Pain at maximal jaw Pain at rest opening Baseline Follow-upBaseline Follow-up Median 19.5 3.5 59.5 6 Mean 33.3 3.7 59.3 27.3 Min 30 8 0 Max 89 16 95 75 S.D. 31.05 4.83 24.73 32.34

At baseline, 2 patients experienced pain every day and 8 patients painseveral times per week. At the follow-up 6 patients had not a singleepisode with pain during the week prior to follow-up, 1 patient had painat one occasion during the week and the remaining 3 patients had painseveral times a week or every day.

What is claimed is:
 1. A method of treating a patient formuskuloskeletal pain, consisting of administering intramuscularly tosaid patient a composition, wherein ropivacaine is the soletherapeutically active ingredient in said composition, and said patientis administered an amount of ropivacaine effective to ameliorate saidmuskuloskeletal pain.
 2. The method of claim 1, wherein said pain ismyofascial pain.
 3. The method of claim 1, wherein said pain is due totendinitis.
 4. The method of any one of claims 1-3, wherein saidropivacaine is in its monohydrate form.
 5. The method of any one ofclaims 1-3, wherein the concentration of administered ropivacaine is1-20 mg/ml.
 6. The method of any one of claims 1-3, wherein theconcentration of administered ropivacaine is 1-10 mg/ml.
 7. The methodof claim 6, wherein the concentration of administered ropivacaine is 2-5mg/ml.